Immunophilins (IP) are receptor proteins having no known cellular function outside their role as receptors for immunosuppressive drugs. Three immunosuppressive drugs that bind to immunophilins are FK506 (Tacrolimus), rapamycin and cyclosporin A, which are used in the treatment of patients after organ transplantation and in selected autoimmune disorders. FK506 and rapamycin are potent immunosuppressive drugs and are activated upon binding to immunophilins designated FK506-binding proteins (FKBPs). Cyclosporin A is of lower potency and higher toxicity than FK506 and rapamycin, and is activated upon binding to cyclophilins. When bound to an immunosuppressive drug, FKBPs and cyclophilins inhibit the activity of calcium-activated phosphatase calcineurin, which leads to inhibition of cytokine synthesis and immunosuppression.
Immunophilins are also known to have peptidyl-prolyl isomerase (PPIase) , or rotamase, enzyme activity. Rotamase catalyzes the interconversion of the cis and trans isomers of peptide and protein substrates for the immunophilin proteins. When immunosuppressive drugs or other compounds are bound to the immunophilins, the rotamase activity of the immunophilins is inhibited, an effect unrelated to the immunosuppressive effect of these drugs or compounds. In fact, many compounds have been developed in the laboratory which have an affinity for immunophilins and which inhibit rotamase activity without inhibition of calcineurin and subsequent immunosuppressive effects. Some of these compounds are described, for example, in U.S. Pat. No. 5,696,135 (Steiner et al.).
FK506 has been shown to augment neurite outgrowth in the presence of nerve growth factor (NGF) in PC 12 cells and in rat and chick sensory ganglia explants and has also been shown to increase the number and length of tyrosine hydroxylase-positive neurites in rodent primary dopamine neuronal cultures. In animal models, the drug and its analogues stimulate axonal re-growth and enhance functional recovery following peripheral nerve and spinal cord injury and have protective and regenerative effects in neurotoxic lesions.
FK506 is an immediately available candidate for therapy in treatment of neurodegenerative diseases. It is a small molecule with ready access to the nervous system, and it has been approved for use in humans by the Food and Drug Administration. FK506 is known to act primarily upon lesioned neurons, while sparing the healthy ones. Importantly, FK506 selectively promotes neuronal population growth while inhibiting glial proliferation and can thus specifically target neuronal regeneration and astrocytosis in patients with neural cell transplants. In contrast, traditional neurotrophic peptides have less specific effects. Neurologic adverse effects (including confusion, seizures, tremors, headache) in large part associated with intravenous administration of FK506 have been found to generally subside with oral use or dosage reduction.
Current grafting strategies for neuronal replacement in patients with chronic neurodegenerative diseases include the implantation of first trimester human fetal neuroglial cells with the hope that neuroprogenitor cells will differentiate and survive as functional neurons. Another strategy involves the use of transfected cells grafted in vivo which are proposed to be a stable source of neurotrophic factors (NTF) which promote the survival of residual host neurons. Other treatments include direct delivery in vivo of NTFs, or the use of a NTera-2 teratocarcinoma cell line for grafts, these cells being “neuron-like”. None of these strategies deliver the needed long-term clinical improvement.